Cognitive dysfunction is a major component of depression, and may in fact underlie many of the mood symptoms. Specifically, a deficit in cognitive flexibility, associated with hypoactivity in the medial prefrontal cortex (mPFC), creates negative biases about the self, the world and the future. Chronic stress is also a major risk factor for depression, and we have shown previously that performance on an attentional set-shifting test (AST), which is a measure of prefrontal-dependent cognitive flexibility in rats, is compromised by chronic stress. It is also facilitated by the monoamines, norepinephrine (NE), and serotonin (5-HT), and is responsive to antidepressant drugs that block the reuptake of NE and/or 5-HT. Such drugs are effective antidepressants, but their effectiveness is limited, as partial response and treatment resistance remain significant problems for the treatment of depression. As an alternative to pharmacotherapy, evidence-based psychotherapy, primarily involving cognitive therapy or cognitive-behavioral therapy (CBT), has efficacy comparable to antidepressant drug treatment, and the combination of pharmacotherapy and psychotherapy has efficacy greater than either alone. But little is known about the mechanisms involved. The cognitive set-shifting test, used extensively in the previous funding period to investigate antidepressant drug mechanisms, bears conceptual similarity to CBT, in that it requires rats to modify previously established contingencies based on feedback from a changing environment. Thus, to extend this work, the four specific aims comprising this competing renewal will address the neurobiological mechanisms underlying evidence-based psychotherapy, using cognitive set-shifting as a rat model of CBT. In aim 1, the antidepressant-like effectiveness of this model of CBT will be further established. Chronic unpredictable stress (CUS) will be used to create a deficit of cognitive flexibility. The cognitive set-shifting test will be used as the model of psychotherapy. And to avoid learning effects, a second measure of prefrontal-dependent cognitive flexibility will be used as the dependent measure, the extinction of cue-conditioned fear. In aim 2, based on our past results with antidepressant drugs, the role of 11-adrenergic receptors and 5-HT2A serotonin receptors in mPFC in the beneficial effects of CBT will be investigated, using local microinjections into mPFC. In aim 3, the effectiveness of adjunct treatment with drugs that block reuptake of NE and 5-HT, in combination with CBT, will be studied. And in aim 4, the generality of this model will be tested by switching the roles of the two behavioral tasks - extinction will serve as the model of psychotherapy that engages prefrontal cortex, and set-shifting will be the dependent measure of cognitive flexibility that is compromised by chronic stress. This project addresses the neurobiological mechanisms underlying the efficacy of evidence-based psychotherapy, using a novel rat model of CBT, in the face of chronic stress- induced deficits of cognitive flexibility. The results will therefore generate new knowledge upon which to develop strategies that are more customized, rapid, specific and effective in the treatment of depression. PUBLIC HEALTH RELEVANCE: These preclinical laboratory studies will address neurobiological mechanisms underlying the efficacy of evidence-based psychotherapy, using cognitive set-shifting as a rat model of cognitive-behavioral therapy. They will also address mechanisms underlying the increased efficacy of adjunct treatment, combining antidepressant drugs with psychotherapy. Understanding these processes will lead to new knowledge by which to develop strategies that are more customized, more rapid, more specific and more effective in the treatment of depression.